Benzylic Fluorination Induced by a Charge-Transfer Complex with a Solvent-Dependent Selectivity Switch

We present a divergent strategy for the fluorination of phenylacetic acid derivatives that is induced by a charge-transfer complex between Selectfluor and 4-(dimethylamino)pyridine. A comprehensive investigation of the conditions revealed a critical role of the solvent on the reaction outcome. In the presence of water, decarboxylative fluorination through a single-electron oxidation is dominant. Non-aqueous conditions result in the clean formation of α-fluoro-α-arylcarboxylic acids.


General remarks
Substrates, reagents, and solvents were purchased from commercial suppliers and used without further purification. NMR spectra were recorded using a Varian 400 MHz (400, 100 and 376 MHz respectively for 1 H-, 13 C-and 19 F-NMR) or a Bruker NEO 500 MHz spectrometer equipped with a H/F/C/N-TCI-Prodigy probe and are reported in ppm relative to the residual solvent peaks. Peaks are reported as: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, with coupling constants in Hz. Reaction monitoring via FTIR analysis was performed with a ReactIR TM 15 (Mettler-Toledo) console, with a DST 9.5mm SiComp TM probe attached. Analytical thin layer chromatography (TLC) was carried out using pre-coated TLC-sheets, ALUGRAM Xtra SIL G/UV254 sheets (Macherey-Nagel) and visualized with 254 nm light. Purification of synthesized compounds was carried out by flash chromatography on a Reveleris X2 Flash Chromatography System from GRACE. A prepacked column with 12 g, 40 μm silica gel was used at a 30 mL/min elution flow rate. Silica 60 M (0.04-0.063 mm) silica gel (Macherey-Nagel) was used for dry loading of the crude compounds. High resolution mass spectra (HRMS, m/z) were recorded on a Bruker MicroTOF spectrometer using positive electrospray ionization (ESI).

Decarboxylative fluorination
General experimental procedure for optimization experiments. An oven dried crimp top vial (19 x 100 mm) equipped with a stir bar was charged with with 4-biphenylacetic acid and Selectfluor ® . The solvent mixture was added and the mixture was stirred and sonicated for 5 min. Subsequently, 4dimethylaminopyridine (and, if indicated, the additive) was added. The vial was sealed and the reaction mixture was stirred and sonicated for 5 min. The mixture was degassed by bubbling Argon for 10 min. The reaction mixture was stirred in an oil bath at 70 °C for the respective time. Afterwards, dimethyl maleate (1 equiv.) was added. The reaction mixture was quenched with HCl (1 M, 1 mL) and extracted with CDCl3 (1 mL). An aliquote (~200 μL) of the organic phase was subsequently subjected to 1 H NMR analysis. Figure S1. Example of a 1 H-NMR spectrum for determining NMR yields.    -62  50  2  NaHCO3  33  22  3  Cs2CO3  13  traces  4  Li2CO3  23  traces  5  K2CO3  17  traces  6  KF  84  56  7  CsF  84  62  8  K3PO4  21  traces  9  K2HPO4  42  34  10  LiF  70  56  11  MgF2  64  54  12  CaF2  61  52

Scope
General experimental procedure for the synthesis of 4-(fluoromethyl)-1,1'-biphenyl (1). An oven dried vessel equipped with a stir bar was charged with substrate (424.5 mg, 2 mmol, 0.2 mM) and Selectfluor® (2.13 g, 6 mmol, 3 equiv.). Aceton:H2O (10 mL, 1:1) was added and the mixture was stirred and sonicated for 5 min. Subsequently, 4-dimethylaminopyridine (488.7 mg, 4 mmol, 2 equiv.) and NaF (167.9 mg, 4 mmol, 2 equiv.) were added. The vial was sealed and the reaction mixture was stirred and sonicated for 5 min. The mixture was degassed by bubbling Argon for 10 min. The reaction mixture was stirred in an oil bath at 70 °C for the respective time. The reaction mixture was quenched with HCl (1 M, 10 mL) and extracted with CHCl3 (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over MgSO4 under concentrated under reduced pressure. Purification was performed by column chromatography using hexane. The title compound was isolated as a colorless solid (267.9 mg, 1.44 mmol, 72%). 1  General experimental procedure products that were not isolated due to their low boiling point. An oven dried crimp top vial (19 x 100 mm) equipped with a stir bar was charged with substrate (0.1 mmol, 0.2 mM) and Selectfluor® (0.3 mmol, 3 equiv.). Aceton:H2O (2 mL, 1:1) was added and the mixture was stirred and sonicated for 5 min. Subsequently, 4-dimethylaminopyridine (0.2 mmol, 2 equiv.) and NaF (0.2 mmol, 2 equiv.) were added. The vial was sealed and the reaction mixture was stirred and sonicated for 5 min. The mixture was degassed by bubbling Argon for 10 min. The reaction mixture was stirred in an oil bath at 70 °C for the respective time. Upon completion, dimethyl maleate (12.4 μL, 0.1 mmol, 1 equiv.) was added. The reaction mixture was quenched with HCl (1 M, 1 mL) and extracted with CDCl3 (1 mL). An aliquote (~200 μL) of the organic phase was subsequently subjected to 1 H NMR analysis.

1-(tert-butyl)-4-(fluoromethyl)benzene (2).
The compound was synthesized following the general procedure. An NMR yield of 84% was determined using dimethyl maleate as an internal standard. The product was not isolated due to its low boiling point.

1-(fluoromethyl)-2-methylbenzene (3).
The compound was synthesized following the general procedure. An NMR yield of 80% was determined using dimethyl maleate as an internal standard. The product was not isolated due to its low boiling point.

2-(2-methoxyphenyl)acetic acid (4).
The compound was synthesized following the general procedure. An NMR yield of 56% was determined using dimethyl maleate as an internal standard. The product was not isolated due to its low boiling point.
(Fluoromethyl)benzene (5). The compound was synthesized following the general procedure. An NMR yield of 60% was determined using dimethyl maleate as an internal standard. The product was not isolated due to its low boiling point. S10

1-(fluoromethyl)-4-methylbenzene (6).
The compound was synthesized following the general procedure. An NMR yield of 66% was determined using dimethyl maleate as an internal standard. The product was not isolated due to its low boiling point.

1-bromo-4-(fluoromethyl)benzene (7)
. The compound was synthesized following the general procedure. An NMR yield of 50% was determined using dimethyl maleate as an internal standard. The product was not isolated due to its low boiling point.

1-chloro-4-(fluoromethyl)benzene (8).
The compound was synthesized following the general procedure. An NMR yield of 60% was determined using dimethyl maleate as an internal standard. The product was not isolated due to its low boiling point.

1-(fluoromethyl)-4-(trifluoromethyl)benzene (9).
The compound was synthesized following the general procedure. An NMR yield of 20% was determined using dimethyl maleate as an internal standard. The product was not isolated due to its low boiling point. S12

1-(1-fluoroethyl)-4-isobutylbenzene (10).
The compound was synthesized following the general procedure. An NMR yield of 44% was determined using dimethyl maleate as an internal standard. The product was not isolated due to its low boiling point.

α-fluorination
General experimental procedure for optimization experiments. An oven-dried vessel (19 x 100 mm) equipped with a stir bar was charged with 4-fluorophenylacetic acid (or, if indicated another phenylacetic acid derivative), 4-dimethylaminopyridine and Selectfluor ® . Solvent was added, the vessel was sealed with a septum and sonicated for 5 minutes. The mixture was stirred at room temperature for the respective reaction time. Upon completion, dimethyl maleate (1 equiv.) was added The reaction mixture was quenched with HCl (1 M, 1 mL) and extracted with CDCl3 (1 mL). An aliquote (~200 μL) of the organic phase was subsequently subjected to 1 H NMR analysis. NMR spectra were taken in CDCl3 or MeOD-d3. A representative 1 H NMR spectrum for determining the yield is shown in Figure S2.

Reaction monitoring using a ReactIR
To maintain a constant operating temperature, the ReactIR console was filled with liquid nitrogen every 12 hours. Prior to each experiment, a background spectrum was recorded before attaching the reaction vessel. The raw ReactIR data was treated with a negative second derivative function, to aid in separation of peaks. The reference spectrum of the solvent was subtracted. The product peak appeared at ~1 648 cm -1 (C-H bending, aromatic), Selectfluor was detected at 1005 cm -1 (N-F bond) and the consumption of DMAP was observed at 1608 cm -1 (C=C semicircle stretch). [4][5] Data obtained from the iCiR was processed using OriginPro2021. Figure S4. ReactIR setup shown with reaction vessel attached to the probe. The custom-made sidearm allows the delayed addition of reagents, degassing or sampling.
Experimental procedure for reaction monitoring. A custom-made reaction vessel (19 x 100 mm) with a sidearm ( Figure S4) was equipped with a stir bar and charged with 4-tert-butylphenylacetic acid (115. 35 mg, 0.2 mM, 0.6 mmol) and 4-dimethylaminopyridine (146.6 mg, 1.2 mmol, 2 equiv.). MeCN (3 mL) was added, the vessel was sealed and sonicated for 5 minutes. The reaction vessel was attached to a PTFE adapter affixed to the ReactIRs probe ( Figure S3). The reaction mixture was stirred for 30 min while collecting data ( Figure S4). After this period, Selectfluor (255.06 mg, 0.72 mmol, 1.2 equiv.) was added and the mixture was stirred for 1 h at r.t.

NMR experiments
Initial NMR experiments with SelectFluor and DMAP in absence of starting material indicated that HF (signs of glass etching of the NMR tubes). To prevent glass etching and consumption of HF by this process, we used poly propylene micro reaction caps and Teflon NMR inserts for further measurements. DMAP forms an adduct with HF ( Figure S7 and S8). The triplet signal at 11.42 ppm shows a long-range coupling to the pyridinium nitrogen in the 1 H-15 N-HMBC spectrum ( Figure S8). Similar pyridinium polyhydrogen fluorides are known, such as Olahs reagent. 6 Figure S7. 1   In the 1 H NMR spectrum of a mixture of SelectFluor with DMAP, we observed the same triplet signal indicative of a pyridinium HF adduct ( Figure S9 and S10).
The superposition of the 1 H-15 N-HMBC spectra of the DMAP/HF mixture with the reaction mixture of SelectFluor/DMAP shows that, also when using SelectFluor, the pyridinium nitrogen resonance shifts to ca. 160 ppm indicative of the formation of the (F-H-F)-adduct. In this case, however, the (F-H-F)-Triplett is too broad such that the long-range correlation signal could not be detected.  S23 19 F NMR measurements show that HF is liberated very early after mixing the reactants (19F = -166 ppm, see Figure S10). Right after mixing, additional, transient signals (19F = -19 and -14 ppm, respectively) are observed in the 19 F NMR spectrum. These might originate from N-fluorinated species. However, we have not been able to prove this beyond doubt. After a reaction time of (here) several days, these transient signals have disappeared, and the 19 F signal of HF has shifted slightly to (19F = -177 ppm, Figure S11). In this regard, it has to be noted that the 19 F chemical shift of HF depends strongly on its concentration, the presence of H + and other coordinating agents.

S24
Neutralization with NaOH converts HF into F -. Applied to the sample shown in Figure S11, still only two 19 F signals are observed, confirming the presence of BF4and F -( Figure S12). The amount of HF and F -, resp., increases with time. Calibrating the integral of the BF4 --signal to 100%, the integrals of the HF signals change from 20 % (after mixing), 26 % (after 4h) to 28% and reach 25% for the quenched Fsignal. General experimental procedure. An oven-dried vessel (19 x 100 mm) equipped with a stir bar was charged with substrate (1.8 mmol, 1 equiv, 0.2 mM), 4-dimethylaminopyridine (3.6 mmol, 2 equiv.) and Selectfluor. MeCN (9 mL) was added, the vessel was sealed stirred at room temperature for one hour. HCl (10 mL, 1 M) was added and the mixture was extracted with diethylether (3 x 10 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography (SiO2, Hexane/EtOAc or Hexane/MeOH) on a Grace™ Reveleris™ system.